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John W Steele - One of the best experts on this subject based on the ideXlab platform.
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Latrepirdine dimebon a potential alzheimer therapeutic regulates autophagy and neuropathology in an alzheimer mouse model
Autophagy, 2013Co-Authors: John W Steele, S GandyAbstract:Alzheimer disease (AD) is a form of neurodegeneration that develops over the course of multiple decades and as a result of the accumulation of the pathogenic amyloid-β (Aβ) peptide, also known as A4. In late-stage AD, failure of autophagic clearance results in neuronal cell bodies that are almost entirely consumed by autophagic vacuoles (AVs). Previously, we have shown that the potential AD drug Latrepirdine (aka Dimebon®), a Russian antihistamine that has shown mixed results in phase II clinical trials in AD, regulates metabolism of the amyloid-β/A4 precursor protein (APP). In two Molecular Psychiatry papers in 2012, we sought to determine the mechanism through which Latrepirdine regulates APP metabolism and to determine, using an Alzheimer mouse model, whether Latrepirdine provides protection from the toxicity associated with the accumulation of Aβ. In cultured cells, we provided evidence that Latrepirdine stimulates MTOR- and ATG5-dependent autophagy, leading to the reduction of intracellular levels of APP metabolites, including Aβ. Consistent with this finding, we found that chronic Latrepirdine administration resulted in increased levels of the biomarkers thought to correlate with autophagy activation in the brains of TgCRND8 (APP K670M, N671L, V717F) or wild-type mice, and that treatment was associated with abrogation of behavioral deficit, reduction in Aβ neuropathology, and prevention of autophagic failure among TgCRND8 mice.
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Latrepirdine dimebon enhances autophagy and reduces intracellular gfp aβ42 levels in yeast
Journal of Alzheimer's Disease, 2012Co-Authors: John W Steele, Prashant Bharadwaj, Giuseppe Verdile, Renae Barr, Veer Bala Gupta, Lenard M Lachenmayer, Zhenyu Yue, Michelle E EhrlichAbstract:Latrepirdine (Dimebon TM), an anti-histamine, has shown some benefits in trials of neurodegenerative diseases characterized by accumulation of aggregated or misfolded protein such as Alzheimer's disease (AD) and has been shown to promote the removal of α-synuclein protein aggregates in vivo. An important pathway for removal of aggregated or misfolded proteins is the autophagy-lysosomal pathway, which has been implicated in AD pathogenesis, and enhancing this pathway has been shown to have therapeutic potential in AD and other proteinopathies. Here we use a yeast model, Saccharomyces cerevisiae, to investigate whether Latrepirdine can enhance autophagy and reduce levels of amyloid-β (Aβ)42 aggregates. Latrepirdine was shown to upregulate yeast vacuolar (lysosomal) activity and promote transport of the autophagic marker (Atg8) to the vacuole. Using an in vitro green fluorescent protein (GFP) tagged Aβ yeast expression system, we investigated whether Latrepirdine-enhanced autophagy was associated with a reduction in levels of intracellular GFP-Aβ42. GFP-Aβ42 was localized into punctate patterns compared to the diffuse cytosolic pattern of GFP and the GFP-Aβ42 (19 : 34), which does not aggregate. In the autophagy deficient mutant (Atg8Δ), GFP-Aβ42 showed a more diffuse cytosolic localization, reflecting the inability of this mutant to sequester GFP-Aβ42. Similar to rapamycin, we observed that Latrepirdine significantly reduced GFP-Aβ42 in wild-type compared to the Atg8Δ mutant. Further, Latrepirdine treatment attenuated Aβ42-induced toxicity in wild-type cells but not in the Atg8Δ mutant. Together, our findings provide evidence for a novel mechanism of action for Latrepirdine in inducing autophagy and reducing intracellular levels of GFP-Aβ42.
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Acute dosing of Latrepirdine (Dimebon™), a possible Alzheimer therapeutic, elevates extracellular amyloid-β levels in vitro and in vivo
Molecular Neurodegeneration, 2009Co-Authors: John W Steele, Soong H Kim, John R Cirrito, Deborah K Verges, Jessica L Restivo, David Westaway, Paul Fraser, Peter St George Hyslop, Mary Sano, Ilya BezprozvannyAbstract:Background Recent reports suggest that Latrepirdine (Dimebon™, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-β (Aβ) peptide in the brain, and Aβ-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of Latrepirdine on levels of extracellular Aβ using in vitro and in vivo experimental systems. Results We evaluated extracellular levels of Aβ in three experimental systems, under basal conditions and after treatment with Latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + Latrepirdine (500pM-5 μM). Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of Latrepirdine (1 μM or 10 μM). Drug-naïve Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + Latrepirdine (3.5 mg/kg). Picomolar to nanomolar concentrations of acutely administered Latrepirdine increased the extracellular concentration of Aβ in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01), while a clinically relevant acute dose of Latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01). Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, Latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 μM) and led to more modest increases in extracellular Aβ_x-42 levels (+10%; p = 0.001); of note, however, was the observation that extracellular Aβ_x-40 levels did not change. Conclusions Here, we report the surprising association of acute Latrepirdine dosing with elevated levels of extracellular Aβ as measured in three independent neuron-related or neuron-derived systems, including the hippocampus of freely moving Tg2576 mice. Given the reported association of chronic Latrepirdine treatment with improvement in cognitive function, the effects of chronic Latrepirdine treatment on extracellular Aβ levels must now be determined.
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acute dosing of Latrepirdine dimebon a possible alzheimer therapeutic elevates extracellular amyloid β levels in vitro and in vivo
Molecular Neurodegeneration, 2009Co-Authors: John W Steele, Soong H Kim, John R Cirrito, Deborah K Verges, Jessica L Restivo, David Westaway, Paul E Fraser, Peter St George Hyslop, Mary SanoAbstract:Background Recent reports suggest that Latrepirdine (Dimebon™, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-β (Aβ) peptide in the brain, and Aβ-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of Latrepirdine on levels of extracellular Aβ using in vitro and in vivo experimental systems.
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© 2009 Steele et al; licensee BioMed Central Ltd.
2009Co-Authors: John W Steele, John R Cirrito, Deborah K Verges, Jessica L Restivo, David Westaway, Paul Fraser, Soong H. Kim, George Hyslop, Mary SanoAbstract:Research article Acute dosing of Latrepirdine (Dimebon™), a possible Alzheimer therapeutic, elevates extracellular amyloid-β levels in vitro and in viv
J W Steele - One of the best experts on this subject based on the ideXlab platform.
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Latrepirdine molecular mechanisms underlying potential therapeutic roles in alzheimer s and other neurodegenerative diseases
Translational Psychiatry, 2013Co-Authors: Prashant Bharadwaj, Tenielle Porter, David Groth, Ralph N Martins, K A Bates, E Teimouri, G Perry, J W Steele, S GandyAbstract:Latrepirdine (Dimebon TM ) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer’s disease (AD) and Huntington’s disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, Latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of Latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating Latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for Latrepirdine-related class of molecules including the b-carbolines and aminopropyl carbazoles in AD, Parkinson’s disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of Latrepirdine for dementia treatment.
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Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer’s and other neurodegenerative diseases
Translational Psychiatry, 2013Co-Authors: P R Bharadwaj, K A Bates, T Porter, E Teimouri, G Perry, J W Steele, S Gandy, D Groth, R N Martins, Giuseppe VerdileAbstract:Latrepirdine (Dimebon^TM) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer’s disease (AD) and Huntington’s disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, Latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of Latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating Latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for Latrepirdine-related class of molecules including the β-carbolines and aminopropyl carbazoles in AD, Parkinson’s disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of Latrepirdine for dementia treatment.
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Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain
Molecular Psychiatry, 2013Co-Authors: J W Steele, M L Lachenmayer, J Liken, A Stock, S H Kim, L M Delgado, I E Alfaro, S Bernales, G Verdile, P BharadwajAbstract:Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that Latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether Latrepirdine offers protection to Saccharomyces cerevisiae . We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS , and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion ( HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that Latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of Latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that Latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.
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Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model
Molecular Psychiatry, 2013Co-Authors: J W Steele, M L Lachenmayer, J Liken, A Stock, S H Kim, L M Delgado, I E Alfaro, S Bernales, G Verdile, P BharadwajAbstract:Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether Latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aβ42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.
Mary Sano - One of the best experts on this subject based on the ideXlab platform.
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Acute dosing of Latrepirdine (Dimebon™), a possible Alzheimer therapeutic, elevates extracellular amyloid-β levels in vitro and in vivo
Molecular Neurodegeneration, 2009Co-Authors: John W Steele, Soong H Kim, John R Cirrito, Deborah K Verges, Jessica L Restivo, David Westaway, Paul Fraser, Peter St George Hyslop, Mary Sano, Ilya BezprozvannyAbstract:Background Recent reports suggest that Latrepirdine (Dimebon™, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-β (Aβ) peptide in the brain, and Aβ-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of Latrepirdine on levels of extracellular Aβ using in vitro and in vivo experimental systems. Results We evaluated extracellular levels of Aβ in three experimental systems, under basal conditions and after treatment with Latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + Latrepirdine (500pM-5 μM). Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of Latrepirdine (1 μM or 10 μM). Drug-naïve Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + Latrepirdine (3.5 mg/kg). Picomolar to nanomolar concentrations of acutely administered Latrepirdine increased the extracellular concentration of Aβ in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01), while a clinically relevant acute dose of Latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01). Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, Latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 μM) and led to more modest increases in extracellular Aβ_x-42 levels (+10%; p = 0.001); of note, however, was the observation that extracellular Aβ_x-40 levels did not change. Conclusions Here, we report the surprising association of acute Latrepirdine dosing with elevated levels of extracellular Aβ as measured in three independent neuron-related or neuron-derived systems, including the hippocampus of freely moving Tg2576 mice. Given the reported association of chronic Latrepirdine treatment with improvement in cognitive function, the effects of chronic Latrepirdine treatment on extracellular Aβ levels must now be determined.
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acute dosing of Latrepirdine dimebon a possible alzheimer therapeutic elevates extracellular amyloid β levels in vitro and in vivo
Molecular Neurodegeneration, 2009Co-Authors: John W Steele, Soong H Kim, John R Cirrito, Deborah K Verges, Jessica L Restivo, David Westaway, Paul E Fraser, Peter St George Hyslop, Mary SanoAbstract:Background Recent reports suggest that Latrepirdine (Dimebon™, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-β (Aβ) peptide in the brain, and Aβ-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of Latrepirdine on levels of extracellular Aβ using in vitro and in vivo experimental systems.
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© 2009 Steele et al; licensee BioMed Central Ltd.
2009Co-Authors: John W Steele, John R Cirrito, Deborah K Verges, Jessica L Restivo, David Westaway, Paul Fraser, Soong H. Kim, George Hyslop, Mary SanoAbstract:Research article Acute dosing of Latrepirdine (Dimebon™), a possible Alzheimer therapeutic, elevates extracellular amyloid-β levels in vitro and in viv
Brian Corrigan - One of the best experts on this subject based on the ideXlab platform.
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Minimization of CYP2D6 Polymorphic Differences and Improved Bioavailability via Transdermal Administration: Latrepirdine Example
Pharmaceutical Research, 2016Co-Authors: Marci L. Chew, Joyce Mordenti, Thean Yeoh, Gautam Ranade, Ruolun Qiu, Juanzhi Fang, Yali Liang, Brian CorriganAbstract:Purpose Transdermal delivery has the potential to offer improved bioavailability by circumventing first-pass gut and hepatic metabolism. This study evaluated the pharmacokinetics of oral immediate release and transdermal Latrepirdine in extensive and poor CYP2D6 metabolizers (EM/PM). Methods Latrepirdine transdermal solution was prepared extemporaneously. The solution was applied with occlusive dressing to upper or middle back for 24 h. Each subject received a single dose of 8.14 mg oral, 5 mg transdermal, and 10 mg transdermal (EMs only) Latrepirdine free base in a fixed sequence. Results Twelve EMs and 7 PMs (50–79 years) enrolled and completed the study. Latrepirdine was well tolerated following both routes of administration. Dose-normalized Latrepirdine total exposures were approximately 11-fold and 1.5-fold higher in EMs and PMs, respectively following administration of transdermal relative to oral. Differences between EM and PM Latrepirdine exposures were decreased, with PMs having 1.9- and 2.7-fold higher peak and total exposures, respectively, following transdermal administration compared to 11- and 20-fold higher exposures, respectively, following oral administration. Conclusion Transdermal delivery can potentially mitigate the large intersubject differences observed with compounds metabolized primarily by CYP2D6. Transdermal delivery was readily accomplished in the clinic using an extemporaneously prepared solution [NCT00990613].
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minimization of cyp2d6 polymorphic differences and improved bioavailability via transdermal administration Latrepirdine example
Pharmaceutical Research, 2016Co-Authors: Marci L. Chew, Joyce Mordenti, Thean Yeoh, Ruolun Qiu, Juanzhi Fang, Yali Liang, Ranade Gautam Ramchandra, Brian CorriganAbstract:Purpose Transdermal delivery has the potential to offer improved bioavailability by circumventing first-pass gut and hepatic metabolism. This study evaluated the pharmacokinetics of oral immediate release and transdermal Latrepirdine in extensive and poor CYP2D6 metabolizers (EM/PM).
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lackofapharmacokineticinteractionbetweendimebon Latrepirdine anddigoxininhealthysubjects
2010Co-Authors: Ruolun Qiu, Joyce Mordenti, Brian Corrigan, David R Plowchalk, Wonkyung Byon, Steven G Terra, Jenny Fang, Terence FullertonAbstract:3because digoxin is a narrow therapeutic index drug commonly prescribed to elderly patients for the treatment of heart failure and atrial fibrillation. Furthermore, many clinically significant drug-drug interactions occur with digoxin via inhibition of P-glycoprotein (P-gp)-mediated clearance; therefore, digoxin is also recommended by the FDA 4 as a probe P-gp multidrug resistance 1 (MDR1) substrate to evaluate the potential of a new chemical entity for inhibiting P-gp-mediated clearance. • The effects of dimebon on the clinical pharmacokinetic (PK), urinary excretion, and safety of a sensitive P-gp substrate, such as digoxin, are unknown. The aim of this Phase 1 study was to evaluate the potential drug-drug interaction of dimebon with digoxin in healthy subjects. The interaction was assessed at steady-state plasma concentrations for both drugs, when P-gp inhibition was expected to be maximal. The dosing regimen for digoxin was 0.125 mg once daily (QD) for 14 days; this commercially available tablet strength was selected for safety considerations, and is a commonly prescribed dose in elderly patients.
Ralph N Martins - One of the best experts on this subject based on the ideXlab platform.
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the effects of Latrepirdine on amyloid β aggregation and toxicity
Journal of Alzheimer's Disease, 2016Co-Authors: Tenielle Porter, Prashant Bharadwaj, David Groth, Adrian Paxman, Simon M Laws, Ralph N Martins, Giuseppe VerdileAbstract:Latrepirdine (Dimebon) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if Latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:Latrepirdine and with lower concentrations of Latrepirdine. The ability of Latrepirdine to alter the formation of Aβ42 aggregates was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with Latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of Latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which Latrepirdine offers protection. This study investigates the effect of Latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties.
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Latrepirdine molecular mechanisms underlying potential therapeutic roles in alzheimer s and other neurodegenerative diseases
Translational Psychiatry, 2013Co-Authors: Prashant Bharadwaj, Tenielle Porter, David Groth, Ralph N Martins, K A Bates, E Teimouri, G Perry, J W Steele, S GandyAbstract:Latrepirdine (Dimebon TM ) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer’s disease (AD) and Huntington’s disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, Latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of Latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating Latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for Latrepirdine-related class of molecules including the b-carbolines and aminopropyl carbazoles in AD, Parkinson’s disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of Latrepirdine for dementia treatment.